Abstract
The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer’s disease (AD), providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer’s Disease (5XFAD) mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ) plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of old-age dementia
Deposition of amyloid plaques is a characteristic feature of the 5X Familial Alzheimer’s Disease (5XFAD) mouse model [20]
In 22-weekold mice, the general brain morphology of 5XFAD transgenic mice is not affected by plaque deposition as exemplified in the hippocampus and cortex by Nissl staining (Figure 1A, B)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of old-age dementia. Neuritic plaques containing amyloid b (Ab) and neurofibrillary tangles composed of hyperphosphorylated Tau protein constitute major neuropathological hallmarks of AD. The amyloid cascade theory provides a rationale for many features of the disease including the pathological markers, the phenotypes caused by autosomal dominant disease genes, and the risk conferred by the APOE gene status [1]. Increased production of certain Ab species, their aggregation, and deposition as insoluble plaques is regarded as an early and key pathology in the development of AD [2]. Therapeutic strategies to reverse or prevent Ab deposits could lead to partial functional restoration of neural circuits [5]. Most AD treatment approaches aim at prevention or reversal of Ab plaque deposition [6,7]
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